Type 2 Diabetes and Fracture Risk in Older Women

This cohort study evaluates whether poorer skeletal characteristics or worse physical function are associated with the increased fracture risk in women with type 2 diabetes.


Vertebral Fracture Assessment (VFA)
Vertebral fracture assessment using lateral DXA images was used to detect vertebral fractures, which were then categorized and graded using Genant's semi-quantitative system. 16Two qualified medical professionals assessed the vertebral fractures as previously described. 17,18The vertebral fracture diagnosis using VFA had an intra-observer agreement of 98.9%, and for moderate to severe vertebral fractures, the agreement was 100%. 17,18gh-Resolution peripheral Quantitative Computed Tomography (HR-pQCT) In cases where the ipsilateral tibia was fractured, the contralateral side was chosen instead.
Measurements were obtained from the standard ultradistal site (9.5 mm and 22.5 mm from the © 2024 Zoulakis M et al.JAMA Network Open. reference line for the radius and tibia, respectively) and at the distal site (14% of measured bone length, measured from the end plate) of each bone.
At each site, 110 parallel slices, with a nominal isotropic resolution of 82 µm, were obtained which enabled the construction of the 3D bone model.Every stack of images was graded from 1-5 representing the level of image quality.Images with the highest quality were graded 1 and those with the lowest quality were graded 5.As per standard protocol, only images of adequate quality (grades 1-3) were used for further analyses.Image procession generated the following variables: total volumetric BMD (TtBMD, mg/cm 3 ), cortical area (Ct.Ar, mm 2 ), cortical thickness (Ct.Th, mm), cortical volumetric bone mineral density (Ct.BMD, mg/cm 3 ), trabecular bone volume fraction (BV/TV, %), trabecular thickness (Tb.Th, mm), and separation (Tb.Sp, mm).
An Image Processing Language (IPL v5.08b), provided by the manufacturer was utilized for further analysis to obtain variables needed to calculate cortical porosity (Ct.po) which was then calculated using the following equation: cortical pore volume/(cortical pore volume + cortical bone volume.As we have explained in previous publications, 19,20 it was necessary to separate bone tissue and cortical bone from extraosseous tissue and trabecular bone by placing contours in the endosteal and periosteal surface of the cortical bone.Calculations of stiffness (the resistance against deformation) and ultimate failure load were obtained with the use of the manufacturer's finite element analysis with the conversion of voxels to equally sized brick elements.Failure load was defined as the load at which at least 2% of the bone elements exceeded, 7000 microstrains during simulated uniaxial compression.Stiffness, the resistance against deformation, was analyzed.A Young's modulus of 10 GPa and a Poisson ratio of 0.3 were used in the FE models for all participants, as previously described. 21The CVs for measurement of trabecular parameters in the distal radius and distal tibia were 0.4% to 2.5% and 0.8% to 2.6%, respectively.CVs for measurement of cortical parameters in the distal radius and distal tibia were 0.1% to 0.9%.

Bone Microindentation
The Osteoprobe device was not available at the study start but became available later on with measurements of the first women starting in September 2014.From the initial 3028 women, only the latter 1613 were asked to participate and 647 (40% inclusion rate) were accepted to undergo bone micro-indentation.This procedure has been described in more detail previously. 20dentations were performed after application of a local anesthetic, at least 11 indentations were performed at the mid-shaft of the tibia in a circular manner and with a minimum 2 mm distance.
To ensure that the probe was completely established on the cortical surface the first indentation was discarded, the remaining indentations were visually attested and indentations deviating due to technical or mechanical reasons were removed.Five operators in total carried out the procedure and during the first 100 measurements, at least two operators were present to ensure that everyone conducted the process consistently.The intra-observer CV (using the same operator at a different site) was 3.2%, while the inter-observer CV (using different operators) was 5.2%.

Statistical Analyses
Previous osteoporosis medication was defined as previous treatment with oral bisphosphonates, zoledronic acid, denosumab, strontium ranelate, and parathyroid hormone analogs.

eTable 5 .
Characteristics According to Incident Fracture

Fracture Outcomes for Women with T2D vs Controls
adjusted for age and BMI.Model 2: adjusted for age, BMI, and clinical risk factors included in FRAX* and previous treatment with osteoporosis medication.Model 3: all covariates used in model 2 with the addition of femoral neck (FN) BMD, *Previous fracture after 50 years of age, family history of hip fracture, oral glucocorticoid use with at least 5mg daily and for 3 months or more, excessive alcohol intake (21 units per week or more), current smoking, secondary osteoporosis, and rheumatoid arthritis.©2024 Zoulakis M et al.JAMA Network Open.eTable 3.

Baseline Characteristics According to Incident Fracture
2024 Zoulakis M et al.JAMA Network Open.eTable 6.

Fracture Outcomes for Women With T2D vs. Controls Without Previous Osteoporosis Treatment
Hazard ratios (HR) and 95% Confidence Interval, Cox proportional hazard models Unadjusted model, Model 1: adjusted for age and BMI.Model 2: adjusted for age, BMI, and clinical risk factors included in FRAX*.Model 3: all covariates used in model 2 with the addition of femoral neck (FN) BMD, *Previous fracture after 50 years of age, family history of hip fracture, oral glucocorticoid use with at least 5mg daily and for 3 months or more, excessive alcohol intake (21 units per week or more), current smoking, secondary osteoporosis, and rheumatoid arthritis.eTable 9.

Fractures and Mortality per Tertile of HbA1c The
distribution of Hba1c and fractures or mortality is presented per tertile of HbA1c.The HR according to tertile of HbA1c (with the 1 st tertile as reference) is presented for MOF, any fracture, hip fracture, and death.The Cox models are fully adjusted (age, BMI, CRFs, and FN BMD).Abbreviations: HbA1c=glycated hemoglobin; MOF=major osteoporotic fracture.a= HbA1c units of measurement = (mmol/mol), b=896.FN=Femoral Neck.The number of events is presented according to diabetes groups.The associations between diabetes and mortality are results from fully adjusted Cox proportional hazards models.Adjusted or age, BMI, FRAX clinical factors, previous osteoporosis medication, and femoral neck BMD.Abbreviation: CI = confidence interval, T1= First Tertile, T2 = Second Tertile, T3= Third Tertile.

eTable 11. Fine and Gray Subdistribution Hazard Ratios for T2D Women vs Controls
SHR) hazard ratios for T2D women vs controls for fractures while considering the competing risk of death calculated using a Fine and Gray model.Multivariable adjustments for age, sex, BMI, femoral neck BMD, previous treatment with osteoporosis medication and clinical risk factors included in FRAX (previous fracture after 50 years of age, family history of hip fracture, oral glucocorticoid use with at least 5mg daily and for 3 months or more, excessive alcohol intake (21 units per weekor more), current smoking, secondary osteoporosis, and rheumatoid arthritis).